IgG, Subclass 2

Elevated IgG subclass 2 levels can indicate a variety of underlying conditions and may have different implications depending on the clinical context. To provide a comprehensive understanding, let's delve into the immunoglobulin G (IgG) subclasses, their functions, potential causes for elevation, associated conditions, diagnostic approaches, and possible treatment options.

Understanding IgG and Its Subclasses:

Immunoglobulin G (IgG) is the most abundant type of antibody in the blood and extracellular fluid, playing a crucial role in the body's immune response against infections. IgG is divided into four subclasses: IgG1, IgG2, IgG3, and IgG4, each with distinct functions and distributions.

→ IgG1: Predominantly involved in responses to protein antigens.

→ IgG2: Primarily responds to polysaccharide antigens and is important in the defense against bacterial infections.

→ IgG3: Known for its ability to activate complement and is involved in responses to protein antigens.

→ IgG4: Generally associated with chronic exposure to antigens and has a role in allergy and tolerance mechanisms.

Elevated IgG Subclass 2 Levels:

When IgG subclass 2 levels are elevated, it suggests an abnormal immune response, which can be caused by various factors.

Potential Causes and Associated Conditions:

→ Chronic Infections: 

• Bacterial Infections: Chronic bacterial infections, particularly those involving encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae), can lead to elevated IgG2 levels. This is due to the body's ongoing response to polysaccharide antigens.
• Other Infections: Persistent viral or fungal infections can also stimulate IgG2 production as part of a broader immune response.

→ Autoimmune Diseases:

• Conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and other autoimmune disorders can result in elevated IgG2 levels due to the body's immune system mistakenly targeting its own tissues.

→ Allergic Reactions:

• Although IgG4 is more commonly associated with allergies, chronic allergic conditions and long-term antigen exposure can sometimes lead to an increase in IgG2 levels as part of an overall immune dysregulation.

→ Immunodeficiency Disorders:

• Paradoxically, certain primary immunodeficiency disorders, like Common Variable Immunodeficiency (CVID), may present with elevated IgG2 levels as part of a compensatory mechanism in response to recurrent infections.

→ Chronic Inflammatory Conditions:

• Conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP) or inflammatory bowel disease (IBD) can involve elevated IgG2 levels due to ongoing inflammation and immune activation.

Diagnostic Evaluation:

When elevated IgG2 levels are detected, a thorough diagnostic workup is essential to determine the underlying cause:

1. Clinical History and Physical Examination:

   • Detailed history of infections, autoimmune symptoms, allergies, and chronic conditions.
   • Physical examination to identify signs of infection, inflammation, or systemic disease.

2. Laboratory Tests:

   • Complete Blood Count (CBC): To check for signs of infection or hematologic abnormalities.
   • Comprehensive Metabolic Panel (CMP): To assess liver and kidney function.
   • Inflammatory Markers: Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to evaluate inflammation.
   • Autoantibody Testing: For autoimmune diseases (e.g., ANA, rheumatoid factor).
   • Specific Infection Testing: Cultures, serology, or PCR for suspected infections.

3. Immunological Tests:

   • Quantitative Immunoglobulins: To measure levels of IgG, IgA, IgM, and their subclasses.
   • Functional Antibody Testing: To assess the body’s response to specific vaccines or infections.

Treatment Options:

Treatment for elevated IgG2 levels focuses on addressing the underlying cause:

1. Infections:

   • Antibiotics: For bacterial infections.
   • Antiviral or Antifungal Therapy: For viral or fungal infections.
   • Vaccination: To prevent recurrent infections, especially in immunocompromised individuals.

2. Autoimmune Diseases:

   • Immunosuppressive Medications: Such as corticosteroids, methotrexate, or biologics to reduce immune system activity.
   • Disease-Modifying Antirheumatic Drugs (DMARDs): Specifically for conditions like rheumatoid arthritis.

3. Allergies:

   • Antihistamines: To manage symptoms.
   • Allergen Immunotherapy: To reduce sensitivity to allergens over time.

4. Immunodeficiency Disorders:

   • Immunoglobulin Replacement Therapy: Intravenous or subcutaneous immunoglobulin (IVIG/SCIG) to provide necessary antibodies.
   • Prophylactic Antibiotics: To prevent infections in individuals with recurrent infections.

5. Chronic Inflammatory Conditions:

   • Anti-Inflammatory Medications: Such as nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids.
   • Targeted Biologic Therapies: For specific conditions like IBD or CIDP.

Elevated IgG subclass 2 levels can be a marker of various underlying conditions, including chronic infections, autoimmune diseases, allergies, immunodeficiency disorders, and chronic inflammatory conditions. A comprehensive diagnostic approach is essential to identify the underlying cause, and treatment should be tailored accordingly. Managing the underlying condition often leads to normalization of IgG2 levels and improved patient outcomes. If you or someone you know has elevated IgG2 levels, consulting a healthcare provider specializing in immunology or infectious diseases is recommended for a detailed evaluation and appropriate management.

- People with persistently low levels of one or two IgG subclasses and a normal total IgG level have a selective IgG subclass deficiency.

- People with IgG subclass deficiency require more extensive diagnostic evaluation including the demonstration of a poor antibody response to vaccine challenge before one is diagnosed with a clinically significant IgG subclass deficiency necessitating specific treatment that may include Ig replacement therapy.

- IgG subclass deficiencies may be associated with other immunoglobulin abnormalities. One common pattern is IgG2 and IgG4 subclass deficiency associated with IgA deficiency.

- IgG subclass deficiencies are also an integral component of other well-known primary immunodeficiency diseases, such as Wiskott-Aldrich Syndrome and Ataxia-Telangiectasia. 

- IgG subclass deficiencies are sometimes associated with poor or partial responses to pneumococcal polysaccharides, specifically IgG2 deficiency with or without IgG4 deficiency.

IgG1 deficiency:

Selective IgG1 deficiency is very rare, as it is usually associated with deficiency of either IgG3, or other immunoglobulin classes, such as in common variable immunodeficiency. Isolated IgG1 deficiency has been reported in chronic fatigue syndrome. As IgG1 is the most abundant IgG subclass, its deficiency often results in hypogammaglobulinemia.

IgG1 and IgG3 deficiency:

People with this combination are commonly present with infections of the lower airways, which can progress to chronic lung disease. 

IgG2 and IgG4 deficiency:

Conversely, IgG2 and IgG4 deficiencies manifest in the form of otitis media and sinusitis. IgG2 deficiency is the most common type of IgG subclass deficiency, either as an isolated finding or together with IgG4 deficiency. People with this defect have recurrent infections with encapsulated bacteria such as Streptococcus pneumonia and/or Haemophilus influenza type B. IgG2 deficiency often results in infectious complications, such as bronchiectasis, bronchopneumonia, bronchitis, obstructive lung disease, and asthma. It has also been associated with ataxia telangiectasia and systemic lupus erythematosus (SLE). Children with SLE and IgG2 and IgG4 deficiency may present with cardiac tamponade, instead of the more common nephropathy and arthritis. The impact of decreased concentration of IgG4 cannot be easily assessed, since IgG4 may be present in low concentrations in healthy children. Nevertheless, it was shown that low concentrations of IgG4 are present in a large percentage of patients with recurrent respiratory tract infections.

Possible symptoms:

People with any form of IgG subclass deficiency occasionally suffer from recurrent respiratory infections similar to the ones seen in other antibody deficiency syndromes, chiefly infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae. An increased frequency of viral upper respiratory infections may not be an indication of antibody deficiency. Therefore, it is critical to distinguish between infections caused by respiratory viruses from those due to bacterial pathogens.

A few people with IgG subclass deficiency may appear very similar to patients with severe immunoglobulin deficiencies. Rarely, IgG subclass deficient patients may have recurrent episodes of bacterial meningitis or infections of the bloodstream (sepsis).

Diagnosis:

The finding of an IgG subclass deficiency should prompt reevaluation over a period of months before determining that the patient is truly immunodeficient. Subclass deficiencies need to be carefully interpreted taking into account the clinical status of the patient as well as the person’s ability to produce specific antibodies in response to vaccines.

Measurement of IgG subclasses can be recommended in the presence of known associated abnormalities, particularly if recurrent infections are also present. 

These circumstances include:

- IgA deficient patients with recurrent infections to determine if there is an associated IgG2 and IgG4 subclass deficiency

- Wiskott-Aldrich and Ataxia-Telangiectasia patients at the onset of recurrent infections

- Specific Antibody Deficiency patients with normal total immunoglobulins

Possible treatment:

- Recurrent or chronic infections of the ears, sinuses and lungs need comprehensive treatment to prevent permanent damage that might result in hearing loss or chronic lung disease. It is also important to encourage patients to continue normal activities of daily living, such as school or work.

- The mainstay of treatment includes appropriate use of antibiotics to treat and prevent infections. The type and severity of infection usually determines the type of antibiotic used and the length of treatment. 

- Ig therapy is an option for selected symptomatic patients that have persistent IgG subclass deficiencies, documented poor responses to polysaccharide vaccines and who fail prophylactic antibiotic therapy. The decision to begin Ig replacement therapy needs to be carefully discussed with the healthcare provider

- People with frequent infections and persistent IgG subclass deficiencies with normal anti-polysaccharide antibodies should also be treated using adequate prevention, vaccine and antibiotic therapy, perhaps even considering the use of Ig replacement if other treatment fails.